Process for preparing 1,3-dioxolane derivatives

ABSTRACT

This invention provides an improved process for the preparation of compounds of formula (I): ##STR1## wherein: n is 0, 1 or 2; 
     each R 1  is independently halo or lower alkyl; 
     R 2  is nitro or --N(R 3 )R 4  where 
     R 3  is hydrogen or lower alkyl; 
     R 4  is hydrogen, lower alkyl, lower alkylsulfonyl or --C(Y)R 5  where Y is oxygen or sulfur and R 5  is hydrogen, lower alkyl, lower alkoxy or --N(R 6 )R 7  where R 6  is hydrogen or lower alkyl and R 7  is hydrogen, lower alkyl or lower alkoxycarbonyl; or 
     R 3  and R 4  together with N is pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, wherein the piperazino is optionally substituted at the 4-position by --C(O)R 8  where R 8  is hydrogen, lower alkyl, lower alkoxy or amino; 
     or pharmaceutically acceptable salts thereof. These compounds are useful in treating disease-states characterized by hypercholesterolemia.

This is a division of pending application Ser. No. 07/900,568, filedJun. 18, 1992, incorporated herein by reference, and now U.S. Pat. No.5,208,331.

FIELD OF THE INVENTION

This invention relates to an improved process for the preparation andseparation of individual stereoisomers of certain 1,3-dioxolanederivatives useful in treating mammals having disease-statescharacterized by hypercholesterolemia.

BACKGROUND OF THE INVENTION

Processes for the preparation of compounds of formula (I): ##STR2##wherein n is 0, 1 or 2;

each R¹ is independently halo or lower alkyl;

R² is nitro or --N(R³)R⁴ where

R³ is hydrogen or lower alkyl;

R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl or --C(Y)R⁵ where Y isoxygen or sulfur and R⁵ is hydrogen, lower alkyl, lower alkoxy or--N(R⁶)R⁷ where R⁶ is hydrogen or lower alkyl and R⁷ is hydrogen, loweralkyl or lower alkoxycarbonyl; or

R³ and R⁴ together with N is pyrrolidino, piperidino, morpholino,thiomorpholino or piperazino, wherein the piperazino is optionallysubstituted at the 4-position by --C(O)R⁸ where R⁸ is hydrogen, loweralkyl, lower alkoxy or amino;

or a pharmaceutically acceptable salt thereof; are described, interalia, in co-pending U.S. patent application Ser. No. 07/633,599, filedDec. 20, 1990, the disclosure of which is incorporated in full herein byreference.

The compounds of formula (I), including their pharmaceuticallyacceptable salts, and the compositions containing them, inhibitcholesterol synthesis and are therefore useful in treatingdisease-states characterized by hypercholesterolemia. In particular,compounds of formula (I) inhibit cholesterol synthesis by inhibitinglanosterol 14α-demethylase, a cytochrome P-450 enzyme. Compounds offormula (I) are also more effective in inhibiting lanosterol14α-demethylase than they are in inhibiting other cytochrome P-450enzymes, for example, the cytochrome P-450 enzymes which contribute togonadal and adrenal steroidogenesis and cholesterol degradation. Thus,the compounds of formula (I) are useful in treating disease-statescharacterized by hypercholesterolemia with minimum effect on thephysiological functions of key cytochrome P-450 enzymes.

SUMMARY OF THE INVENTION

In general, the present invention is directed to an improved andefficient process for the preparation of single stereoisomers ofcompounds of formula (I) and their pharmaceutically acceptable salts. Inthe previously disclosed preparation of the compounds of formula (I) theindividual stereoisomers were separated by the conventional method offlash chromatography, e.g., elution with 0.1% NH₄ OH and 5% methanol,which was gradually changed to a solution of 0.2% NH₄ OH and 10%methanol, in a 3:3:2 mixture of ethyl acetate, methylene chloride andhexane. One of the advantages that the present invention has over thepreviously disclosed preparation of the compounds of formula (I) is theease at which intermediates of compounds of formula (I) are separatedout from a mixture of stereoisomers. This is accomplished through thecrystallization of the nitrate salts of the undesired stereoisomers,i.e., the trans-stereoisomers which correspond to the desiredcis-stereoisomers. Upon formation, the nitrate salts of the undesiredtrans-stereoisomers precipitate out from the reaction mixture leavingthe desired cis-stereoisomers in the mother liquor for furtherprocessing.

The process of the instant invention also allows for the undesiredtrans-stereoisomers to be recycled back into the process describedherein. This is accomplished through the re-equilibration of theundesired trans-stereoisomers to a mixture of the trans- andcis-stereoisomers. This mixture can then be further treated as describedabove to separate out the desired cis-stereoisomers from the undesiredtrans-stereoisomers.

Accordingly, the present invention has several different aspects to it.In one aspect, the present invention provides a process for thepreparation of compounds of formula (I): ##STR3## wherein: n is 0, 1 or2;

each R¹ is independently halo or lower alkyl;

R² is nitro or --N(R³)R⁴ where

R³ is hydrogen or lower alkyl;

R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl or --C(Y)R⁵ where Y isoxygen or sulfur and R⁵ is hydrogen, lower alkyl, lower alkoxy or--N(R⁶)R⁷ where R⁶ is hydrogen or lower alkyl and R⁷ is hydrogen, loweralkyl or lower alkoxycarbonyl; or

R³ and R⁴ together with N is pyrrolidino, piperidino, morpholino,thiomorpholino or piperazino, wherein the piperazino is optionallysubstituted at the 4-position by --C(O)R⁸ where R⁸ is hydrogen, loweralkyl, lower alkoxy or amino;

or a pharmaceutically acceptable salt thereof; which process comprisesthe following steps:

(1) reacting the compound of formula (B): ##STR4## with a compound offormula (D): ##STR5## wherein R⁹ is halo, tosylate or mesylate, in thepresence of a strong acid selected from the group consisting ofalkanesulfonic acids, arenesulfonic acids and Lewis acids, to yield amixture of stereoisomers represented by the following formula (E):##STR6## wherein R⁹ is halo, tosylate or mesylate; (2) dissolving themixture of stereoisomers represented by formula (E), as defined above,in a suitable solvent and treating the resulting solution with about 0.5to about 2.0 molar equivalents of concentrated nitric acid to yield acompound of formula (Eb): ##STR7## wherein R⁹ is halo, tosylate ormesylate, as a precipitate; (3) treating the mother liquor resultingfrom the preparation of the compound of formula (Eb) with a suitablebase and allowing the resulting mixture to crystallize from a suitablesolvent to yield a compound of formula (Ea): ##STR8## wherein R⁹ ishalo, tosylate or mesylate; and (4) treating a compound of formula (Ea),as defined above, with a compound of formula (F): ##STR9## wherein n is0, 1 or 2;

each R¹ is independently halo or lower alkyl;

R² is nitro or --N(R³)R⁴ where

R³ is hydrogen or lower alkyl;

R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl or --C(Y)R⁵ where Y isoxygen or sulfur and R⁵ is hydrogen, lower alkyl, lower alkoxy or--N(R⁶)R⁷ where R⁶ is hydrogen or lower alkyl and R⁷ is hydrogen, loweralkyl or lower alkoxycarbonyl; or

R³ and R⁴ together with N is pyrrolidino, piperidino, morpholino,thiomorpholino or piperazino, wherein the piperazino is optionallysubstituted at the 4-position by --C(O)R⁸ where R⁸ is hydrogen, loweralkyl, lower alkoxy or amino;

in the presence of base to yield a compound of formula (I), as definedabove.

In another aspect, the present invention provides for the recycling ofthe compounds of formula (Eb) so formed as starting materials for themixture of stereoisomers represented by formula (E) as described above.This recycling comprises the following additional steps to the processdescribed above:

(5) treating the compound of formula (Eb) so formed with a suitable baseto yield a compound of formula (Ec): ##STR10## wherein R⁹ is halo,tosylate or mesylate; and (6) treating the compound of formula (Ec) soformed with a strong acid selected from the group consisting ofalkanesulfonic acids, arenesulfonic acids and Lewis acids, to yield themixture of stereoisomers represented by formula (E), as defined above inStep (1).

The mixture of stereoisomers as represented by formula (E) so formed bythis recycling process can then be further treated as described above inSteps (2), (3) and (4) of the process to produce the compounds offormula (I).

In another aspect, the present invention provides for the preparation ofcompounds of formula (B) for use in Step (1) of the process describedherein. The preparation comprises treating the compound of formula (A):##STR11## with dimethyl sulfoxide, which has been activated by anorganic nitrogenous base-sulfur trioxide complex, in the presence of anorganic base to yield the compound of formula (B).

In another aspect, the present invention provides for the separation ofcompounds of formula (Ea): ##STR12## wherein R⁹ is halo, tosylate ormesylate, from a mixture of stereoisomers represented by the followingformula (E): ##STR13## wherein R⁹ is halo, tosylate or mesylate; whichprocess comprises the following steps:

(a) dissolving the mixture of stereoisomers represented by formula (E),as defined above, in a suitable solvent and treating the resultingsolution with about 0.5 to about 1.5 molar equivalents of concentratednitric acid to yield a compound of formula (Eb): ##STR14## wherein R⁹ ishalo, tosylate or mesylate, as a precipitate; and (b) treating themother liquor resulting from the preparation of the compound of formula(Eb) with a suitable base and then allowing the resulting mixture tocrystallize from a suitable solvent to yield a compound of formula (Ea),as defined above.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

The term "lower alkyl" refers to a straight or branched chain monovalentradical consisting solely of carbon and hydrogen, containing nounsaturation and having from one to four carbon atoms, e.g., methyl,ethyl, n-propyl, 1-methylethyl, n-butyl, 2,2-dimethylpropyl(tert-butyl), 1-methylpropyl, and the like.

The term "lower alkoxy" refers to a radical of the formula --OR_(a)where R_(a) is lower alkyl as defined above, e.g., methoxy, ethoxy,n-propoxy, 1-methylethoxy, n-butoxy,2,2-dimethylpropoxy (tert-butoxy),and the like.

The term "halo" refers to a halogen radical, e.g., fluoro, chloro, bromoor iodo.

The term "amino" refers to the radical --NH₂.

The term "lower alkanesulfonyl" refers to a radical of the formula--S(O)₂ R_(a) where R_(a) is lower alkyl as defined above, e.g., mesyl(methanesulfonyl), ethanesulfonyl, n-propanesulfonyl, n-butanesulfonyl,iso-butanesulfonyl, and the like.

The term "lower alkoxycarbonyl" refers to the radical of the formula--C(O)R_(b) where R_(b) is lower alkoxy as defined above, e.g.,methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl,2-methylpropoxycarbonyl, and the like.

The term "aryl" refers to a phenyl or naphthyl radical optionallysubstituted by lower alkyl, e.g., 4-methylphenyl (p-tolyl),3-methylphenyl (m-tolyl), and the like.

The term "optionally" means that the subsequently described event orcircumstance may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances whereinit does not.

The term "alkanesulfonic acid" refers to an acid of the formula R_(a)S(O)₂ OH where R_(a) is lower alkyl as defined above, e.g.,methanesulfonic acid, ethanesulfonic acid, and the like. This termincludes those alkanesulfonic acids which are covalently bonded to aninert polymer for stability and ease of handling.

The term "arenesulfonic acid" refers to an acid of the formula R_(c)S(O)₂ OH where R_(c) is aryl as defined above, e.g., p-toluenesulfonicacid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, and thelike. This term includes those arenesulfonic acids which are covalentlybonded to an inert polymer for stability and ease of handling.

The term "tosylate" refers to a radical of the formula --OS(O)₂ R_(d)where R_(d) is 4-methylphenyl (p-tolyl).

The term "mesylate" refers to a radical of the formula --OS(O)₂ CH₃.

The term "organic nitrogenous base-sulfur trioxide complex" refers to acomplex of the formula R_(e).SO₃ where R_(e) is an organic nitrogenousbase selected from the group consisting of tertiary amines, e.g.,triethylamine, trimethylamine, diisopropylethylamine, and the like; andcyclic amines, e.g., pyridine, pyrrolidine, morpholine,N-methylmorpholine, N-methylpyridine and the like. This term includesthose organic nitrogenous base-sulfur trioxide complexes which arecovalently bonded to an inert polymer for stability and ease ofhandling.

The term "mother liquor" refers to the residual solution which remainsafter the precipitation of a compound of formula (Eb) in Step (2) of theprocess described herein.

The term "concentrated nitric acid" refers to 68% to 72% aqueous nitricacid.

The term "stereoisomers" refers to compounds having identical molecularformulae and nature or sequence of bonding but differing in thearrangement of their atoms in space.

For purposes of Steps (1) and (6) of the process disclosed herein, theterm "strong acid" refers to alkanesulfonic acids, as defined above,e.g., methanesulfonic acid; arenesulfonic acids, as defined above, e.g.,p-toluenesulfonic acid; and Lewis acids, e.g., titanium tetrachlorideand aluminum chloride. The term also refers to those alkysulfonic acids,arenesulfonic acids and Lewis acids which are covalently bond to aninert polymer for stability and ease of handling.

For purposes of Step (2) of the process disclosed herein wherein themixture of stereoisomers represented by formula (E) is dissolved in asuitable solvent, the term "suitable solvent" refers to those solventswhich are capable of dissolving the mixture of stereoisomers representedby formula (E) and which allow for the precipitation of thecorresponding compound of formula (Eb).

For purposes of Step (3) of the process disclosed herein wherein themother liquor resulting from the preparation of the compound of formula(Eb) is treated with a suitable base, the term "suitable base" refers tothose bases capable of raising the pH of the mother liquor to a pH ofbetween about 10-11, preferably to a pH of about 10. Exemplary of suchsuitable bases include, but are not limited to, sodium hydroxide andtriethylamine.

For purposes of Step (3) of the process disclosed herein wherein theresulting mixture from the basification of the mother liquor is allowedto crystallize from a suitable solvent, the term "suitable solvent"refers to those solvents which are capable of dissolving the resultingmixture and which allow for the crystallization of the compound offormula (Ea). Exemplary of such solvents are ketones, e.g., acetone;alcohols, e.g., isopropanol; ethers, e.g., diethyl ether; and esters,e.g., ethyl acetate; and combinations of two or more of such solvents.The preferred suitable solvent for the crystallization is isopropanol.

For purposes of Step (4) of the process wherein a compound of formula(Ea) is treated with a compound of formula (F) to yield a compound offormula (I), the term "base" refers to an inorganic base strong enoughto allow for the formation of the anion of the compound of formula (F)during the reaction disclosed therein. Exemplary of such a base ispotassium carbonate.

For purposes of Step (5) of the process wherein a compound of formula(Eb) is treated with a suitable base to form a compound of formula (Ec),the term "suitable base" refers to those bases capable of raising the pHof the solution containing the compound of formula (Eb) to a pH ofbetween 9-11, preferably to a pH of about 10. Exemplary of such basesinclude, but are not limited to, sodium hydroxide andN-methylmorpholine.

The term "inert solvent" refers to a solvent inert under the conditionsof the reaction being described in conjunction therewith, e.g., benzene,toluene, methylene chloride, acetonitrile, hexane, tetrahydrofuran("THF"), xylene, and the like.

For purposes of the oxidation of the compound of formula (A) to yield acompound of formula (B), the term "organic base" refers to tertiaryamines, e.g., trimethylamine, triethylamine, diisopropylethylamine,N-methylmorpholine, and the like.

For clarification purposes, Steps (a) and (b) of the process forseparating a compound of formula (Ea) from a mixture of stereoisomersrepresented by formula (E), as set forth above in the Summary of theInvention, are essentially the same reaction steps as Steps (2) and (3)of the process for preparing compounds of formula (I), as set forthabove in the Summary of the Invention.

For purposes of converting the compounds of formula (I) intocorresponding pharmaceutically acceptable salts, the term "acid" refersto those acids capable of forming stable pharmaceutically acceptablesalts of the compounds of formula (I), e.g., hydrochloric acid, oxalicacid, nitric acid, sulfuric acid, maleic acid, methanesulfonic acid, andthe like; preferably hydrochloric acid.

"Pharmaceutically acceptable salt" refers to those salts which retainthe biological effectiveness and properties of the free bases, which arenot biologically or otherwise undesirable, and which are formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like.

It is understood, for purposes of this invention, that the compounds offormula (I) do not include those compounds wherein n is 2 and the two R¹substituents are adjacent tert-butyl groups.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

The nomenclature used herein is basically a modified form of I.U.P.A.C.nomenclature wherein compounds of formula (I), and intermediatesthereof, are named as derivatives of 1,3-dioxolane. The followingnumbering system will be used for naming the compounds: ##STR15##

The compounds of formula (I), their pharmaceutically acceptable salts,and intermediates thereof, have at least two asymmetric carbon atoms intheir structure, namely the 2-carbon and 4-carbon of the dioxolane ring,and therefore can exist as distinct stereoisomers. All suchstereoisomers, and their pharmaceutically acceptable salts, are intendedto be within the scope of this invention.

Compounds of formula (I) have the substituent at the 2-position of thedioxolane ring and the substituent at the 4-position of the dioxolanering on the same side of the plane of the dioxolane ring, and aredesignated herein as the cis-stereoisomers. The correspondingtrans-stereoisomers are those compounds which have the substituent atthe 2-position of the dioxolane ring and the substituent at the4-position of the dioxolane ring on opposite sides of the plane of thedioxolane ring.

An absolute descriptor, R or S, may be assigned to the chiral carbonatoms in the individual stereoisomers according to the "Sequence Rule"procedure of Cahn, Ingold and Prelog.

For example, a compound of formula (I) wherein n is 0 and R² is --NH₂,i.e., the compound of the following formula: ##STR16## is named hereinas(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-aminophenylthio)methyl-1,3-dioxolane.

PREFERRED EMBODIMENTS

Among the compounds of formula (I) and their pharmaceutically acceptablesalts, as described above in the Summary of the Invention, a preferredgroup of compounds prepared by the process disclosed herein are thosecompounds of formula (I) wherein n is 0.

A preferred subgroup of these compounds are those compounds of formula(I) wherein R² is in the 4-position and is --N(R³)R⁴ where R³ ishydrogen or lower alkyl and R⁴ is hydrogen, lower alkyl, loweralkylsulfonyl or --C(Y)R⁵ where Y is oxygen or sulfur and R⁵ ishydrogen, lower alkyl, lower alkoxy or --N(R⁶)R⁷ where R⁶ is hydrogen orlower alkyl and R⁷ is hydrogen, lower alkyl or lower alkoxycarbonyl.

A preferred class of these compounds are those compounds of formula (I)wherein R³ is hydrogen and R⁴ is hydrogen or --C(Y)R⁵ where Y is oxygenand R⁵ is hydrogen, lower alkyl or lower alkoxy.

A preferred subclass of these compounds are those compounds of formula(I) wherein R⁴ is hydrogen or acetyl.

Presently, the most preferred compounds of formula (I) prepared by theprocess disclosed herein are the following:(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-aminophenylthio)methyl-1,3-dioxolane; and(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-acetamidophenylthio)methyl-1,3-dioxolane.Particularly preferred are the pharmaceutically acceptable salts ofthese compounds, particularly those formed with hydrochloric acid.

Within the process described herein, several reagents and conditions arepreferred. For example, in Step (1) of the process, it is preferred touse compounds of formula (D) where R⁹ is tosylate. In addition, in Step(1) it is preferred that the strong acid is selected from the groupconsisting of methanesulfonic acid and p-toluenesulfonic acid. It isparticularly preferred to use methanesulfonic acid in Step (1).

It is also preferred that in Step (2) of the process the amount ofconcentrated nitric acid used to treat compounds of formula (E) isbetween about 0.8 and about 1.0 molar equivalents.

It is also preferred to recycle the compounds of formula (Eb) so formedin the process by treating such compounds with a suitable base to yieldthe corresponding free bases, i.e., the compounds of formula (Ec), andto further treat these compounds of formula (Ec) so formed withmethanesulfonic acid to yield a mixture of stereoisomers as representedby formula (E), which can then be further treated as in Step (2) of theprocess described above in order to separate out the compounds offormula (Ea) from the mixture of stereoisomers represented by formula(E).

It is also preferred to prepare the compound of formula (B) used in theprocess described herein by treating a compound of formula (A) withdimethyl sulfoxide, which has been activated by a trimethylamine-sulfurtrioxide complex, in the presence of an organic base, preferablytriethylamine.

Presently, the preferred process of the invention involves thepreparation of compounds of formula (I): ##STR17## wherein: n is 0;

R² is --N(R³)R⁴ where R³ is hydrogen and R⁴ is hydrogen or --C(Y)R⁵where Y is oxygen and R⁵ is methyl, or a pharmaceutically acceptablesalt thereof;

which preparation comprises the following steps:

(1) reacting the compound of formula (B): ##STR18## with a compound offormula (D): ##STR19## wherein R⁹ is tosylate, in the presence ofmethanesulfonic acid, to yield a mixture of stereoisomers represented bythe following formula (E): ##STR20## wherein R⁹ is tosylate; (2)dissolving the mixture of stereoisomers represented by formula (E), asdefined above, in a suitable solvent and treating the resulting solutionwith about 0.8 to about 1.0 molar equivalents of concentrated nitricacid to

yield a compound of formula (Eb): ##STR21## wherein R⁹ is tosylate, as aprecipitate; (3) treating the mother liquor resulting from thepreparation of the compound of formula (Eb) with sodium hydroxide andthen allowing the resulting mixture to crystallize from isopropanol toyield a compound of formula (Ea): ##STR22## wherein R⁹ is tosylate; (4)treating a compound of formula (Ea), as defined above, with a compoundof formula (F): ##STR23## wherein n is 0; and

R² is --N(R³)R⁴ where R³ is hydrogen and R⁴ is hydrogen or --C(Y)R⁵where Y is oxygen and R⁵ is methyl;

in the presence of potassium carbonate to yield a compound of formula(I), as defined above.

It is more preferred that the compound prepared by this process is(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)-methyl-4-(4-aminophenylthio)methyl-1,3-dioxolane,or the corresponding dihydrochloride salt thereof.

It is also more preferred to recycle the compound of formula (Eb) formedin this process back into the process by treating such compound withsodium hydroxide to yield a compound of formula (Ec); which can then betreated with methanesulfonic acid to yield the mixture of stereoisomersrepresented by formula (E).

It is also more preferred that the compound of formula (B) used in thisprocess is prepared by treating a compound of formula (A) with dimethylsulfoxide, which has been activated by a trimethylamine-sulfur trioxidecomplex, in the presence of triethylamine, to yield a compound offormula (B).

Preparation of Compounds of Formula (I) A. Preparation of StartingMaterials

The compound of formula (B) is a starting material in the preparation ofcompounds of formula (I). It can be prepared by methods disclosed inco-pending U.S. patent application Ser. No. 07/633,599, or by methodsknown to one of ordinary skill in the art, for example, by the method ofSwern using dimethyl sulfoxide activated by, e.g., oxalyl chloride (see,e.g., J. Org. Chem. (1979), Vol. 44, NO. 23, p. 4148. Alternatively, thecompound of formula (B) can be prepared as shown in the followingReaction Scheme 1: ##STR24##

In general, a compound of formula (B) may be prepared by this ReactionScheme by treating a compound of formula (A) with dimethyl sulfoxide(DMSO), which has been activated by an organic nitrogenous base-sulfurtrioxide complex, in the presence of an organic base. The startingcompound of formula (A) may be prepared according to the methodsdescribed in U.S. Pat. Nos. 4,518,607 and 4,078,071 (Syntex); or by themethods described in J. Med. Chem. (1978), Vol. 21, p. 840, and J. Amer.Chem. Soc. (1930), Vol. 52, p. 1164; or by the method described inco-pending U.S. patent application Ser. No. 07/633,599. The organicnitrogenous base-sulfur trioxide complexes are commercially available,for example, from Aldrich Company, or can be prepared by methods knownto those of ordinary skill in the art (see, e.g., "The Reactions ofSulfur Trioxide, and of Its Adducts, with Organic Compounds," Chem. Rev.(1962), Vol. 62, pp. 550-555).

In particular, the compound of formula (A) is treated with an excess ofDMSO, which has been activated with about 2 to 5 molar equivalents,preferably abut 2.25 molar equivalents, of an organic nitrogenousbase-sulfur trioxide complex, e.g., trimethylamine-sulfur trioxidecomplex or pyridine-sulfur trioxide complex, preferablytrimethylaminesulfur trioxide complex. This reaction is carried out inthe presence of an excess amount of an organic base, e.g., preferablytriethylamine, and in an inert solvent, preferably methylene chloride,at a temperature of about 20°-40° C., preferably at about 36°-38° C.,for about 10-24 hours, preferaby for about 16 hours. The compound offormula (B) is then isolated from the reaction mixture by conventionalmeans, preferably by extraction or filtration.

Compounds of formula (D), i.e., 3-chloro-1,2-propanediol acetonide,S-solketal tosylate and S-solketal mesylate, are also starting materialsin the preparation of compounds of formula (I). One compound of formula(D), i.e., S-solketal tosylate, is commercially available, e.g., fromFluka, International Bio-Synthetics (IBIS) or Chemi S.p.A. The compoundsof formula (D) can also be prepared by methods known to those ofordinary skill in the art. For example, the tosylate and the mesylatecan be prepared by treating the corresponding R-solketal with tosyl ormesyl chloride in the presence of excess organic base, such as pyridine,to yield the corresponding S-solketal tosylate and S-solketal mesylate.3-chloro-1,2-propanediol acetonide may be prepared fromS-3-chloro-1,2-propanediol by standard ketalization methods known tothose of ordinary skill in the art, e.g., acid catalyzed ketalization ortrans-ketalization reaction.

B. Preparation of Intermediates

Compounds of formulae (Ea) and (Eb) are intermediates in the preparationof compounds of formula (I) and are prepared as shown in the followingReaction Scheme 2 wherein R⁹ is halo, tosylate or mesylate: ##STR25##

In general, compounds of formulae (Ea) and (Eb) are prepared by firsttreating the compound of formula (B) with a compound of formula (D)wherein R⁹ is halo, tosylate or mesylate, in the presence of a strongacid, to yield the mixture of stereoisomers represented by formula (E)wherein R⁹ is halo, tosylate or mesylate. The compound of formula (E) isthen treated with concentrated nitric acid to yield a compound offormula (Eb) as a precipitate. The resulting mother liquor is thentreated with a suitable base and the resulting mixture is then allowedto crystallize from a suitable solvent to yield a compound of formula(Ea).

In particular, the compound of formula (B) is treated with excess molarequivalants, preferably about 1.25 molar equivalents, of a compound offormula (D) wherein R⁹ is halo, tosylate or mesylate, in the presence ofa strong acid, e.g., an alkanesulfonic acid, an arenesulfonic acid or aLewis acid, preferably methanesulfonic acid, in a suitable solvent,preferably methylene chloride, while maintaining the temperature of thereaction mixture at about 15°-30° C., preferably room temperature. Thereaction mixture is heated to about 30°-40° C. and stirred at thattemperature for about 2-6 hours, preferably for about 3 hours. Thereaction mixture is then allowed to cool to room temperature andconcentrated. The residue is then dissolved in a suitable solvent,preferably ethyl acetate. The resulting solution is then made basic (pH9-11) by a suitable base, preferably sodium hydroxide to form the freebase, i.e., a compound of formula (E). The compound of formula (E) soformed is then treated with about 0.5 to about 2.0 molar equivalents ofconcentrated nitric acid, preferably 0.8 to about 1.0 molar equivalentsof concentrated nitric acid. The resulting slurry is then allowed tostand at 20°-40° C., preferably at 27°-30° C., for about 1 to 4 hours,preferably for about 1 to 2 hours. The corresponding compound of formula(Eb), which is the nitrate salt of the undesired trans-stereoisomer, isisolated by filtration as a precipitate. The mother liquor from thefiltration is then made basic (pH of between 8-11, preferably between9-11) by the addition of a suitable base, preferably sodium hydroxide.The solvent is removed by conventional methods, preferably bydistillation, and the resulting residue is dissolved in a suitablesolvent, preferably isopropanol, and then the corresponding compound offormula (Ea), which is the desired cis-stereoisomer, is isolated fromthe solution by crystallization at room temperature, preferably at19°-21° C., for about 1 to 4 hours, preferably for about 1 to 2 hours.

Alternatively, a solution of a compound of formula (B) in an inertsolvent, preferably methylene chloride, is concentrated by conventionalmethods, preferably by distillation (azeotropic drying). The resultingmixture is then treated with a strong acid, preferably methanesulfonicacid, and 1.0 to 2.0 molar equivalents, preferably 1.25 molarequivalents, of a compound of formula (D). The resulting mixture isstirred at 30°-50° C., preferably at 35°-40° C., for about 2 to 4 hours,preferably for about 3 hours, and then allowed to cool to roomtemperature. Water and an inert solvent, preferably hexane, is thenadded to the mixture and the resulting solution is made basic (pH ofbetween 9 and 13, preferably between 12-13) by the addition of asuitable base, preferably sodium hydroxide. The corresponding compoundof formula (E) is then isolated from the mixture by conventionalmethods, preferably by concentration of the solution and crystallizationfrom an inert solvent, preferably hexane. The compound of formula (E) isthen dissolved in a suitable solvent, preferably ethanol, and thentreated with a 0.5 to 2.0 molar equivalents of concentrated nitric acid,preferably 0.8 to 1.0 molar equivalents of concentrated nitric acid, at35°-45° C., preferably at 40°-43° C., for about 0.5 to about 3 hours,preferably for about 0.5 to 1.5 hours. The corresponding compound offormula (Eb) precipitates out and the mother liquor from theprecipitation is made basic by the addition of a suitable base,preferably sodium hydroxide. The solvent is removed by conventionalmethods, preferably by vacuum distillation. The resulting residue isdissolved in a water-immiscible solvent, such as methylene chloride, andthe resulting solution concentrated. The corresponding compound offormula (Ea) is then crystallized from a suitable solvent, preferablyisopropanol.

C: Reequilibration of Compounds of Formula (Eb)

Compounds of formula (Eb) can be recycled back into the reactionillustrated in Reaction Scheme 2 above by reequilibrating the compoundsof formula (Eb) so formed to the mixture of compounds represented byformula (E) as shown in the following Reaction Scheme 3 where R⁹ ishalo, tosylate or mesylate: ##STR26##

In general, compounds of formula (Eb), which are the nitrate salts ofthe undesired trans-stereoisomers formed in process illustrated inReaction Scheme 2, are treated with a suitable base to yield thecompounds of formula (Ec), which are the undesired trans-stereoisomersin their free base form. Compounds of formula (Ec) are then treated witha strong acid to form the mixture of cis-stereoisomers andtrans-stereoisomers represented by formula (E). This mixture can then beintroduced into the reaction illustrated in Reaction Scheme 2 andtreated in the same manner as described therein to produce the separatestereoisomers, i.e., compounds of formulae (Ea) and (Eb). For example,the mixture can be treated with about 0.5 to about 1.5 molar equivalentamount, preferably with about 0.8 to about 1.0 molar equivalent amountof concentrated nitric acid, to form the compound of formula (Eb), whichis the nitrate salt of the undesired trans-stereoisomer; and theresulting mother liquor can then be treated with a suitable base and theresulting mixture allowed to crystallize from a suitable solvent toyield a compound of formula (Ea).

In particular, a compound of formula (Eb) is dissolved in an inertsolvent, preferably methylene chloride, and the resulting solution isthen made basic (pH of between 9-11, preferably about 10) by theaddition of a suitable base, preferably sodium hydroxide orN-methylmorpholine. The free base form of the compound of formula (Eb),i.e., the compound of formula (Ec), is then isolated by conventionalmethods, preferably by concentration. The compound of formula (Ec) isthen treated with an excess molar equivalents, preferably 4 to 8 molarequivalents, of a strong acid selected from the group consisting ofalkanesulfonic acids and Lewis acids, methanesulfonic acid, at 15°-30°C., preferably at 15°-25° C. The resulting solution is then heated at37°-40° C. for about 1-6 hours, preferably for about 3-6 hours, and thenallowed to cool to room temperature. The corresponding mixture ofstereoisomers represented by formula (E) is then isolated from thesolution by conventional methods, preferably by removal of the solventthrough distillation. This mixture is then treated in a similar manneras described above in Section B to produce the separate stereoisomers,i.e. compounds of formulae (Ea) and (Eb).

Alternatively, the compound of formula (Ec) can be treated with anexcess molar equivalents, preferably about 1.25 to 2.0 molarequivalents, of an arenesulfonic acid, such as p-toluenesulfonic acid,to form the mixture of stereoisomers represented by formula (E). Thisreaction is carried out at reflux temperatures in a high-boilingsolvent, such as xylenes, and in the presence of a higher boilingalcohol, for example, n-butanol.

D. Preparation of compounds of formula (I)

Compounds of formula (I) are prepared from compounds of formulae (Ea)and (F) as shown in the following Reaction Scheme 4 wherein n, R¹, andR² are as defined above in the Summary of the Invention and R⁹ is halo,tosylate or mesylate: ##STR27##

In general, compounds of formula (Ea) are treated with a compound offormula (F) in the presence of a base in an inert solvent to yield acompound of formula (I).

Compounds of formula (F) are commercially available, e.g., from AldrichChemical Co., or may be readily prepared according to methods known toone of ordinary skill in the art, e.g., according to the methodsdescribed in Coll. Czech. Chem. Commun. (1934), Vol. 6, No. 211; J.Amer. Chem. Soc. (1953), Vol. 75, p. 5281; Org. Prep. Procedures (1969),Vol. 1, pp. 87-90; or Chem. Listy (1952), vol. 46, pp. 237-40; or fromthe appropriate substituted phenol by the method described in J. Org.Chem. (1966), Vol. 31, p. 3980, by pyrolysis of the thionecarbamate andhydrolysis of the resulting thiolcarbamate.

In particular, compounds of formula (Ea) are treated with a 1 to 2 molarequivalent amount, preferably a 1.2 molar equivalent of a compound offormula (F) in the presence of a base, preferably anhydrous potassiumcarbonate, in an inert solvent, preferably acetone, and allowed toreflux for about 12-24 hours. The compound of formula (I) is thenisolated from the reaction mixture by conventional methods, for example,distillation, extraction, and crystallization from a suitable solvent,preferably isopropanol.

In summary, compounds of formula (I) and their pharmaceuticallyacceptable salts are prepared by:

(1) reacting the compound of formula (B) with a compound of formula (D)wherein R⁹ is halo, tosylate or mesylate, in the presence of a strongacid to yield a mixture of stereoisomers represented by the formula (E)wherein R⁹ is halo, tosylate or mesylate;

(2) dissolving the mixture of stereoisomers represented by formula (E),as defined above, in a suitable solvent and treating the resultingsolution with about 0.5 to about 2.0 molar equivalents of concentratednitric acid to yield a compound of formula (Eb);

(3) treating the mother liquor resulting from the preparation of thecompound of formula (Eb) with a suitable base and allowing the resultingmixture to crystallize from a suitable solvent to yield a compound offormula (Ea) wherein R⁹ is halo, tosylate or mesylate; and

(4) treating a compound of formula (Ea) wherein R⁹ is halo, tosylate ormesylate, with a compound of formula (F) wherein n is 0, 1 or 2; each R¹is independently halo or lower alkyl; R² is nitro or --N(R³)R⁴ where R³is hydrogen or lower alkyl; R⁴ is hydrogen, lower alkyl, loweralkylsulfonyl or --C(Y)R⁵ where Y is oxygen or sulfur and R⁵ ishydrogen, lower alkyl, lower alkoxy or --N(R⁶)R⁷ where R⁶ is hydrogen orlower alkyl and R⁷ is hydrogen, lower alkyl or lower alkoxycarbonyl; orR³ and R⁴ together with N is pyrrolidino, piperidino, morpholino,thiomorpholino or piperazino, wherein the piperazino is optionallysubstituted at the 4-position by --C(O)R⁸ where R⁸ is hydrogen, loweralkyl, lower alkoxy or amino, to form a compound of formula (I) asdefined above in the Summary of the Invention.

Furthermore, the mixture of stereoisomers represented by formula (E) maybe prepared by:

(5) treating the compound of formula (Eb) so formed in the above processwith a suitable base to yield a compound of formula (Ec) wherein R⁹ ishalo, tosylate or mesylate;

(6) treating the compound of formula (Ec) so formed with a strong acidto yield the mixture of stereoisomers represented by formula (E).

In addition, all compounds of formula (I) that exist in the free baseform may be converted to their pharmaceutically acceptable salts bytreatment with the appropriate inorganic or organic acid. Salts of thecompounds of formula (I) can also be converted to the free base form orto another salt.

The following specific examples are provided as a guide to assist in thepractice of the invention, and are not intended as a limitation on thescope of the invention.

EXAMPLE 1 Preparation of Compounds of Formula (B) (Reaction Scheme 1)

A. To a mixture of 1-(4-(4-chlorophenyl)-2-hydroxybutyl)-imidazole (9.0kg, 35.9 mol) and trimethylaminesulfur trioxide complex, 2.25equivalents (11.25 kg, 80.9 mol), was added triethylamine (45 L, 32.7kg, 323 mol), dimethyl sulfoxide (40.5 L, 44.5 kg, 570 mol), andmethylene chloride (18 L). The resulting mixture was heated to 36°-38°C. and stirred for a minimum of 16 hours. Reaction completion wasmonitored by thin layer chromatography (10% methanol/methylenechloride+2% NH₄ OH). Upon completion of reaction, the reaction mixturewas cooled to 20°-22° C. The temperature was maintained below 27° C.while 40.5 liters of water were added over a period of 15 to 30 minutes.Hexane (54 L) was then slowly added over a period of 15 to 30 minutes at20°-25° C. Water (81 L) was then added to the mixture over a period of30-60 minutes while the temperature was maintained at 20°-25° C. Theresulting mixture was allowed to stand at 20°-22° C. for 1 to 2 hours.The mixture was filtered and the filter cake washed twice with water andthen twice with hexane and dried under vacuum at 48°-51° C. to afford4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one, 8.30 kg (93% yield).

B. Alternatively, a mixture of1-(4-(4-chlorophenyl)-2-hydroxybutyl)imidazole (1.8 kg, 7.18 mol), 2.25equivalents of pyridine-sulfur trioxide complex and methylene chloride(8.6 L) stirred in the presence of excess dimethyl sulfoxide (19 L) andtriethylamine (9 L) at 20°-35° C. for 3 hours. Upon completion ofreaction, the mixture was combined with water (76 L) and hexane (34.4L). The product was isolated, washed with water and hexane and dried toyield 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one, 1.48 kg (83%yield).

EXAMPLE 2 Preparation of Compounds of Formula (D)

A. To a solution of p-toluenesulfonyl chloride (17.16 kg, 90.1 mol) inpyridine (15 L, 14.7 kg, 185 mol) at 25° C. was added 12 kg ofR-solketal (90.9 mol) over 2 to 3 hours with moderate (15°-25° C.)cooling such that the temperature of the reaction mixture rose to33°-37° C. and maintained in this range. The reaction mixture wasstirred for 3 hours at 33°-37° C. Reaction completion was monitored byTLC (1:1 ethyl acetate/hexane). Water (90 L) and ethyl acetate (198 L)was added and the reaction mixture was stirred for 15 minutes. Theorganic layer was washed with dilute hydrochloric acid and water and thesolvent removed under reduced pressure. The residue was redissolvedtwice in 72 L of toluene and the solvent removed under reduced pressureto yield S-solketal tosylate, 25.3 kg (97% yield).

B. In a similar manner, but replacing p-toluenesulfonyl chloride withmethanesulfonyl chloride, S-solketal mesylate is made.

EXAMPLE 3 Preparation of Compounds of Formulae (Ea) and (Eb) (ReactionScheme 2)

A. To a solution of 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one(16.0 kg, 64.3 mol) in methylene chloride (69.5 L) was addedmethanesulfonic acid (28 L, 41.4 kg, 431 mol) while the temperature ofthe reaction mixture was maintained at 18°-25° C. S-Solketal tosylate(23.0 kg, 80.4 mol) was added to the reaction mixture while thetemperature of the reaction mixtures was maintained at 18°-25° C. Thereaction mixture was heated to 35°-40° C. and stirred for 3 hours andthen overnight at 20°-22° C. Reaction completion was monitored by TLC(7% CH₃ OH/CH₂ Cl2+2% NH₄ OH). The solvent was removed under reducedpressure and the residue cooled to 20°-22° C. The residue was thendissolved in ethyl acetate (300 L) and cooled to 10° C. The solution wasthen made basic (pH 10-11) by aqueous sodium hydroxide. The organiclayer was washed with aqueous sodium chloride and dried over anhydroussodium sulfate overnight. Concentrated nitric acid (70%, 3.661 L, 57.5mol), was added to the solution and the resulting slurry was allowed tostand at 27°-30° C. for 1 to 2 hours. The solution was filtered and thefilter cake washed twice with ethyl acetate (70 L) and dried at 40°-45°C. to yield(2R,4S)-trans-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)methyl-1,3-dioxolanenitrate salt (compound of formula (Eb)), 13.42 kg (38.6 yield). Themother liquors from the filtration were combined and made basic (pH9-10) with aqueous sodium hydroxide (50%). The organic layer was washedwith water and the solvent removed by distillation at atmosphericpressure while the ethyl acetate was replaced with isopropanol until thepot temperature reached 83° C. and the ethyl acetate content was in therange of 1.0% to 1.5% and the final volume was about 115 liters. Thesolution was allowed to cool for 30 minutes, and if crystallization hadnot commenced the solution would be seeded with the desired product. Thesolution was allowed to crystallize at 19°-21° C. for 1 to 2 hours, thenfiltered to give(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolane(compound of formula (Ea)), 9.26 kg (30.2% yield).

B. In a similar manner, but replacing4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one with other appropriatelysubstituted compounds of formula (B), the following compounds offormulae (Ea) and (Eb) are made:

(2R,4S)-trans-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(methanesulfonyloxy)methyl-1,3-dioxolane nitrate salt;

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(methanesulfonyloxy)methyl-1,3-dioxolane;

(2R,4S)-trans-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-chloromethyl-1,3-dioxolanenitrate salt; and

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-chloromethyl-1,3-dioxolane.

C. Alternatively, a solution of4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one (1.5 kg, 6.04 mol) andmethylene chloride (35 L) was concentrated to about 5.0 L bydistillation (azeotropic drying). The solution was treated withmethanesulfonic acid (3.7 kg) and S-solketal tosylate (2.2 kg, 7.7 mol)at 35°-40° C. for 3 hours and then overnight at 20°-22° C. Uponcompletion of reaction, the product was mixed with methylene chlorideand water and made basic (pH 12-13) with sodium hydroxide. The organiclayer was washed with water, concentrated and the crude productcrystallized from hexane. The slurry was aged for 1 hour at 19°-23° C.The product (a compound of formula (E)) was isolated, washed with hexaneand dried. The product (2.6 kg) was dissolved in ethanol and treatedwith 0.35 L of 70% nitric acid at 40°-43° C. for 0.5-1.5 hours.(2R,4S)-trans-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolanenitrate salt was isolated, washed with ethanol and dried (39% yield).The mother liquors were combined, basified (pH 9-10) with aqueous sodiumhydroxide, and ethanol was removed by distillation under reducedpressure. The product was extracted into methylene chloride and washedwith water. The organic layer, which was dried over sodium sulfate, wasconcentrated and the product was crystallized from isopropanol; productseeds may be added if necessary. The slurry was aged for at least 1 hourat 19°-22° C. The product,(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolane (compound of formula (Ea)) was isolated, washed withisopropanol and dried (31% yield).

D. Alternatively, a mixture of4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one (1.05 kg, 4.22 mol),p-toluenesulfonic acid monohydrate (0.9 kg) and toluene (14 L) was driedby azeotropic distillation and refluxed with S-solketal tosylate (1.5kg, 5.24 mol) and n-butanol (0.8 L) in a suitable glass vessel. Uponcompletion of reaction, the mixture was concentrated, basified (pH 9)with triethylamine and mixed with ethyl acetate and water. The organiclayer was washed with water, concentrated and the crude productcrystallized by the addition of hexane (25 L) at 20°-25° C. The productwas isolated, washed with hexane, and dissolved in ethanol (20 L),treated with excess concentrated nitric acid (0.29 L) and aged for0.25-0.5 hour at 20°-22° C.

(2R,4S)-trans-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)methyl-1,3-dioxolane nitrate salt was isolated, washed with ethanol andhexane and dried (43% yield). The mother liquors were combined andbasified (pH 9) with triethylamine and decolorized by treatment withcharcoal. Ethanol was removed by distillation under reduced pressure andthe product was mixed with ethyl acetate and water. The organic layerwas washed with water, dried over sodium sulfate and concentrated andthe product crystallized from isopropanol (5 L), with the aid of productseeds if necessary. The slurry was aged for at least 1 hour at 19°-22°C. The product,(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolane(compound of formula (Ea)) was isolated, washed with isopropanol andhexane and dried (24% yield).

EXAMPLE 4 Reequilibration of Compounds of Formula (Eb) (Reaction Scheme3)

A. A mixture of(2R,4S)-trans-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)methyl-1,3-dioxolanenitrate salt (13.99 kg, 25.9 mol), methylene chloride (119 L, 159 kg)and water (21.3 L) was made basic (pH 10) with sodium hydroxide (50%,2.28 L). The organic layer was washed with water, dried over sodiumsulfate, and concentrated to about 42.8 L by distillation to yield asolution of the corresponding free base, i.e.,(2R,4S)-trans-2-(2-(4-chlorophenyl)-ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)-methyl-1,3-dioxolane(compound of formula (Ec)). To this solution was added methanesulfonicacid (16.7 kg, 11.3 L, 173 mol) at 15°-25° C. The resulting solution washeated for 3 hours at 37°-40° C. under nitrogen and allowed to stirovernight at 20°-22° C. Reaction completion was monitored by TLC (7% CH₃OH in CH₂ Cl₂ +2% NH₄ OH). The methylene chloride was removed bydistillation to yield the corresponding mixture of stereoisomers, i.e.,(2RS,4S)-2-(2-(4-chlorophenyl)-ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)-methyl-1,3-dioxolane(compound of formula (E)). Ethyl acetate (120 L, 108 kg) was added tothe residue and the resulting solution was cooled to 10° C. and madebasic (pH 10) with aqueous sodium hydroxide. The organic layer waswashed with aqueous sodium chloride and dried over anhydrous sodiumsulfate. Concentrated nitric acid (70%, 1.490 L, 23.4 mol), was added tothe solution and the resulting solution was allowed to stand at 27°-30°C. for 1 to 2 hours. The solution was filtered and the filter cakewashed twice with ethyl acetate (28.5 L) and dried at 40°-45° C. toyield(2R,4S)-trans-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)methyl-1,3-dioxolanenitrate salt (compound of formula (Eb)), 5.43 kg (39.0 yield). Themother liquors from the filtration were combined and made basic (pH 10)with aqueous sodium hydroxide (50%). The organic layer was washed withwater and the solvent removed by distillation at atmospheric pressurewhile the ethyl acetate was replaced with isopropanol until the pottemperature reached 83° C. and the ethyl acetate content was in therange of 1.0% to 1.5% and the final volume was about 43.3 liters. Thesolution was allowed to cool for 30 minutes, and if crystallization hadnot commenced the solution would have been seeded with the desiredproduct. The solution was allowed to crystallize at 19°-21° C. for 1 to2 hours, then filtered to give(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolane(compound of formula (Ea)), 4.58 kg (37.2% yield).

B. Alternatively, a solution of(2R,4S)-trans-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)-methyl-1,3-dioxolanenitrate salt (1.1 kg, 2.03 mol), methylene chloride (8 L) and water wasmade basic (pH 9-10) with N-methylmorpholine; the organic layer waswashed with water and concentrated with the aid of toluene. The productwas refluxed with S-solketal tosylate (0.05 kg, 0.17 mol), predriedp-toluenesulfonic acid (0.7 kg,), xylene (5.5 L) and n-hexanol (0.35 L).Upon completion of reaction, the mixture was made basic withN-methylmorpholine and concentrated under reduced pressure; the productwas extracted into methylene chloride and washed with water. The organiclayer was dried over sodium sulfate, concentrated, and dissolved inethanol and treated with excess 70% nitric acid (0.26 L). The product,(2R,4S)-trans-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolanenitrate salt, was isolated, washed with ethanol and hexane and dried(36% yield). The mother liquors were combined and basified (pH 10 ) withtriethylamine; ethanol was removed by distillation under reducedpressure and the product was mixed with methylene chloride and water.The organic layer was washed with water, dried over sodium sulfate andconcentrated. The product was crystallized from isopropanol. The slurrywas aged for at least 1 hour at 19°-22° C. The product,(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolane,was isolated, washed with isopropanol and hexane and dried (13% yield).

C. Alternatively, a solution of(2R,4S)-trans-2-(2-(4-chlorophenyl)-ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)methyl-1,3-dioxolane nitrate salt (0.58 g,1.07 mmol) and methylene chloride (5 mL) was made basic (pH 10) withsodium hydroxide (10%, 2.5 mL). The organic layer was evaporated todryness to yield a cream solid (0.51 g). The cream solid was dissolvedin methylene chloride (5.0 mL) and titanium tetrachloride (0.12 mL, 1.1mmol) was added and the resulting solution stirred at 40° C. for 6hours. The solution was drowned into 2.0 mL of sodium hydroxide (10%)and water and filtered. The organic layer was washed with water, dried,concentrated and replaced with hexane. The resulting precipitate wasfiltered, washed with hexane and air-dried to yield 0.44 g of a creamproduct, i.e., the corresponding mixture of stereoisomers represented byformula (E), which was comprised of 50% of a compound of formula (Ea),i.e.,(2S,4S)-cis-2-(2-(4-chlorophenyl)-ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)-methyl-1,3-dioxolaneand 50% of a compound of formula (Eb). i.e..(2R,4S)-trans-2-(2(4-chlorophenyl)-ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)-methyl-1,3-dioxolane.

EXAMPLE 5 (Reaction Scheme 4)

A. To a solution of(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(p-tolunenesulfonyloxy)methyl-1,3-dioxolane(12.7 kg, 26.6 mol) and anhydrous potassium carbonate (6.6 kg) inacetone (101 L) was added a solution of p-aminothiophenol (3.98 kg,31.84 mol) in acetone (26 L). The resulting solution was refluxed for12-24 hours. Reaction completion was monitored by TLC (7%methanol/methylene chloride, 2% NH₄ OH). The reaction mixture was thenallowed to cool to 30°-35 ° C. Water was added (98.5 L) and the acetoneremoved by distillation under reduced pressure. The remaining reactionmixture was allowed to cool to 20°-25° C. Methylene chloride (127 L) wasadded and the resulting solution stirred for 10-15 minutes. The organiclayer was removed and washed with brine and dried over sodium sulfate.Basic alumina (3.4 kg) was added and the resulting slurry stirred for 1hour. The alumina was removed by filtration. The methylene chloride inthe filtrate was removed by distillation at atmospheric pressure whilebeing replaced by isopropanol until the pot temperature reached 83° C.and the final volume was 76 liters. The solution was allowed to cool for30 minutes, and if crystallization had not commenced the solution wouldhave been seeded with the desired product. The solution was allowed tocrystallize at 20°-22° C. overnight and filtered. The resulting filtercake was washed with isopropanol to give(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-amino-phenylthio)methyl-1,3-dioxolane,10.32 kg (90.2% yield).

B. In a similar manner, but replacing p-aminothiophenol with otherappropriately substituted compounds of formula (F), the followingcompounds of formula (I) are made:

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-acetamidoaminophenylthio)methyl-1,3-dioxolane;

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(3-aminophenylthio)methyl-1,3-dioxolane;

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-amino-2-methylphenylthio)methyl-1,3-dioxolane;

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-(4-acetylpiperazino)phenyl)thio)methyl-1,3-dioxolane;

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(2-pyrrolidinophenylthio)methyl-1,3-dioxolane;

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(2-piperidinophenylthio)methyl-1,3-dioxolane;

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-nitrophenylthio)methyl-1,3-dioxolane;

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-propylaminocarbonylaminophenylthio)methyl-1,3-dioxolane;

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-(4-formylpiperazino)phenylthio)methyl-1,3-dioxolane;and

(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-(4-propionylcarbonylpiperazino)phenylthio)methyl-1,3-dioxolane.

EXAMPLE 6 Salts of Compounds of Formula (I)

A mixture of(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-amino-phenylthio)methyl-1,3-dioxolane(10.3 kg, 24.0 mol), concentrated aqueous hydrochloric acid (4.037 L,49.0 mol), isopropanol (30.9 L) and water (1.33 L) was heated to 60°-70°C. in a suitable glass vessel. The resulting solution was clarified byfiltration, cooled to 42°-44° C. and diluted by the addition of acetone(154.5 L). The slurry was cooled to 19°-23° C. and allowed tocrystallize for at least 2 hours. The slurry was filtered and the filtercake was washed twice with 1:1 acetone/ethyl acetate (41.2 L) and driedat 53°-58° C. under reduced pressure to yield the dihydrochloride saltof(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-(4-aminophenylthio)methyl-1,3-dioxolane,11.25 kg (93.4% yield).

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made and equivalentsmay be substituted without departing from the true spirit and scope ofthe invention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A process for the preparation of compounds offormula (I): ##STR28## wherein: n is 0;R² is --N(R³)R⁴ where R³ ishydrogen and R⁴ is hydrogen or --C(Y)R⁵ where Y is oxygen and R⁵ ismethyl, or a pharmaceutically acceptable salt thereof;which processcomprises the following steps: (1) reacting the compound of formula (B):##STR29## with a compound of formula (D): ##STR30## wherein R⁹ istosylate, in the presence of methanesulfonic acid, to yield a mixture ofstereoisomers represented by the following formula (E): ##STR31##wherein R⁹ is tosylate; (2) dissolving the mixture of stereoisomersrepresented by formula (E), as defined above, in a suitable solvent andtreating the resulting solution with about 0.8 to about 1.0 molarequivalents of concentrated nitric acid to yield a compound of formula(Eb): ##STR32## wherein R⁹ is tosylate, as a precipitate; (3) treatingthe mother liquor resulting from the preparation of the compound offormula (Eb) with sodium hydroxide and then allowing the resultingmixture to crystallize from isopropanol to yield a compound of formula(Ea): ##STR33## wherein R⁹ is tosylate; (4) treating a compound offormula (Ea), as defined above, with a compound of formula (F):##STR34## wherein n is 0; andR² is --N(R³)R⁴ where R⁴ is hydrogen and R⁴is hydrogen or --C(Y)R⁵ where Y is oxygen and R⁵ is methyl; in thepresence of potassium carbonate to yield a compound of formula (I), asdefined above.
 2. The process of claim 1 which further comprisesconverting the compound of formula (I) so formed into a pharmaceuticallyacceptable salt thereof by treating said compound with hydrochloricacid.
 3. The process of claim 2 wherein the compound of formula (I) soformed is the dihydrochloride salt of(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)-methyl-4-(4-aminophenylthio)methyl-1,3-dioxolane.4. The process of claim 1 which further comprises the followingsteps:(5) treating the compound of formula (Eb) so formed with sodiumhydroxide to yield a compound of formula (Ec): ##STR35## wherein R⁹ istosylate; (6) treating the compound of formula (Ec) so formed withmethanesulfonic acid to yield the mixture of stereoisomers asrepresented by formula (E), as defined above in Step (1).
 5. The processof claim 4 which further comprises converting the compound of formula(I) so formed into a pharmaceutically acceptable salt thereof bytreating said compound with hydrochloric acid.
 6. The process of claim 5wherein the compound of formula (I) so formed is the dihydrochloridesalt of(2S,4S)-cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)-methyl-4-(4-aminophenylthio)methyl-1,3-dioxolane.7. The process of claim 4 which further comprises the preparation of thecompound of formula (B); which preparation comprises treating a compoundof formula (A): ##STR36## with dimethyl sulfoxide, which has beenactivated by a trimethylamine-sulfur trioxide complex, in the presenceof triethylamine to yield the compound of formula (B), as defined above.8. A process for separating a compound of formula (Ea): ##STR37##wherein R⁹ is halo, tosylate or mesylate, from a mixture ofstereoisomers represented by the following formula (E): ##STR38##wherein R⁹ is halo, tosylate or mesylate; which process comprises thefollowing steps:(a) dissolving the mixture of stereoisomers representedby formula (E), as defined above, in a suitable solvent and treating theresulting solution with about 0.5 to about 1.5 molar equivalents ofconcentrated nitric acid to yield a compound of formula (Eb): ##STR39##wherein R⁹ is halo, tosylate or mesylate, as a precipitate; (b) treatingthe mother liquor resulting from the preparation of the compound offormula (Eb) with a suitable base and allowing the resulting mixture tocrystallize from a suitable solvent to yield a compound of formula (Ea),as defined above.
 9. The process of claim 8 where, in Step (a), themixture of stereoisomers represented by formula (E) is treated withabout 0.8 to about 1.0 molar equivalents of concentrated nitric acid.10. The process of claim 8 wherein R⁹ is tosylate in the compound offormulae (E), (Ea) and (Eb).